Angiogenesis is a process by which new capillary blood vessels are formed. This process rarely occurs under normal biological condition but it always accompanied by embryogenesis, corpus luteum formation and wound healing. Particularly, angiogenesis plays an important role in tumor metastasis (Folkman J and Klagsburn M, Science, 235(4787), pp. 442-447, 1987).
Angiogenesis procedure consists of four steps, i.e., the 1st step is the dissociation of capillary basal lamina by the action of protease enzyme caused by the stimulation of angiogenic factors, the 2nd step is the migration and proliferation of blood endothelial cells, the 3rd step is the formation of capillary tubes due to the differentiation of blood endothelial cell and the 4th step is the reconstruction of new capillary blood vessels.
There have been reported that angiogenesis process is regulated by various stimulating factors and inhibiting factors, for example, growth factor, cytokine, lipid metabolism substance, cryptogenetic fragments of haemostatic protein etc (Folkman J, Nat. Med., 1(1), pp. 27-31, 1995). Angiogenesis stimulating factors can be divided into several types, for example, mainly, cell growth inducing factor, cytokine having immune activity, hormone and lipid products etc (Bussolino F et al., Trends. Biochem. Sci., 22(7), pp. 251-256, 1997).
However, the stimulating factors have various problems to be applied on clinical use since they act on not only vascular endothelial cell but also the other neighboring cells (Malecki M et al., Gene Ther., Supple 1, pp. S159-169, 2005).
Accordingly, recent research has been focused on founding important gene acting only on blood endothelial cell, in particular, being involved in angiogenesis and new method for treating various disease requiring angiogenesis using by the gene. However, there have not been achieved satisfactory results till now.
Therapeutic angiogenesis is a method for treating ischemic disease by promoting the formation of collateral vessels through administering the angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), developmentally regulated endothelial locus-1 (Del-1), hepatocyte growth factor (HGF), platelet-derived endothelial cell growth factor (PD-EGF), angiopoietin, transforming growth factor (TGF) and epidermal growth factor (EGF) etc or the gene encoding the same, and it has been highlighted as a new method for treating severe ischemic disease which could not been performed to percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) method (Kim D. K. and Kwon H. C., The journal of endocrinology, 16(3), pp. 328-338, 2001).
DKK2, a repressor protein of Wnt protein, has been reported to act as an inhibiting factor or stimulating factor of signaling pathways of Wnt (Wu W et al., Curr. Biol., 10(24), pp. 1611-1614, 2000). It has two specific cysteine-rich domains and is divided into various lengths of connection regions. Particularly, the protein belonged to Dickkopf family highly conserves cystein-2 region between the family members as well as 10 cysteines (Krupnik V E et al., Gene, 238(2), pp. 301-313, 1999). It has been reported that DKK2 is closely correlated with the differentiation of osteoclast (Li X et al., Nat. Genet., 37(9), pp. 945-952, 2005).
However, there has been not reported or disclosed about the effect on stimulating activity of DKK2 on angiogenesis in any of above cited literatures, the disclosures of which are incorporated herein by reference.